Systemic overexpression of matricellular protein CCN1 exacerbates obliterative bronchiolitis in mouse tracheal allografts

Obliterative bronchiolitis (OB) involves airway epithelial detachment, fibroproliferation, and inflammation, resulting in chronic rejection and transplant failure. Cysteine‐rich 61 (CCN1) is an integrin receptor antagonist with a context‐dependent role in inflammatory and fibroproliferative processes. We used a mouse tracheal OB model to investigate the role of CCN1 in the development of lung allograft OB. C57Bl/6 mice received a systemic injection of CCN1‐expressing adenoviral vectors 2 days prior to subcutaneous implantation of tracheal allografts from major MHC‐mismatched BALB/c mice. We treated another group of tracheal allograft recipients with cyclic arginine–glycine–aspartic acid peptide to dissect the role of αvβ3‐integrin signaling in mediating CCN1 effects in tracheal allografts. Allografts were removed 4 weeks after transplantation and analyzed for luminal occlusion, inflammation, and vasculogenesis. CCN1 overexpression induced luminal occlusion (P < 0.05), fibroproliferation, and smooth muscle cell proliferation (P < 0.05). Selective activation of αvβ3‐integrin receptor failed to mimic the actions of CCN1, and blocking failed to inhibit the effects of CCN1 in tracheal allografts. In conclusion, CCN1 exacerbates tracheal OB by enhancing fibroproliferation via an α_vβ₃‐integrin‐independent pathway. Further experiments are required to uncover its potentially harmful role in the development of OB after lung transplantation.     

Intralesional bleomycin as alternative therapy in the treatment of multiple basal cell carcinomas

An 82-year-old female with with multiple basal cell carcinomas is presented. Her history includes treatment for similar lesions for 15 years with surgical and X-ray methods. We injected intralesional bleomycin to eight new histologically proven basal cell cancers. A followup at 2 years demonstrates the effectiveness of this therapy.     

Enhancing Racial/Ethnic Equity in College Student Mental Health Through Innovative Screening and Treatment

Although college campuses are diversifying rapidly, students of color remain an underserved and understudied group. Online screening and subsequent allocation to treatment represents a pathway to enhancing equity in college student mental health. The purpose of the current study was to evaluate racial/ethnic differences in mental health problems and treatment enrollment within the context of a largescale screening and treatment research initiative on a diverse college campus. The sample was comprised of n?=?2090 college students who completed an online mental health screening survey and were offered either free online or face-to-face treatment based on symptom severity as a part of a research study. A series of ordinal, binomial and multinomial logistic regression models were specified to examine racial/ethnic differences in mental health problems, prior treatment receipt, and enrollment in online and face-to-face treatment through the campus-wide research initiative. Racial/ethnic differences in depression, anxiety and suicidality endorsed in the screening survey were identified. Students of color were less likely to have received prior mental health treatment compared to non-Hispanic white students, but were equally likely to enroll in and initiate online and face-to-face treatment offered through the current research initiative. Rates of enrollment in online therapy were comparable to prior studies. Online screening and treatment may be an effective avenue to reaching underserved students of color with mental health needs on college campuses. Digital mental health tools hold significant promise for bridging gaps in care, but efforts to improve uptake and engagement are needed.

     

Ex vivo intracoronary gene transfer of adeno‐associated virus 2 leads to superior transduction over serotypes 8 and 9 in rat heart transplants

Heart transplant gene therapy requires vectors with long‐lasting gene expression, high cardiotropism, and minimal pathological effects. Here, we examined transduction properties of ex vivo intracoronary delivery of adeno‐associated virus (AAV) serotype 2, 8, and 9 in rat syngenic and allogenic heart transplants. Adult Dark Agouti (DA) rat hearts were intracoronarily perfused ex vivo with AAV2, AAV8, or AAV9 encoding firefly luciferase and transplanted heterotopically into the abdomen of syngenic DA or allogenic Wistar–Furth (WF) recipients. Serial in vivo bioluminescent imaging of syngraft and allograft recipients was performed for 6 months and 4 weeks, respectively. Grafts were removed for PCR‐, RT‐PCR, and luminometer analysis. In vivo bioluminescent imaging of recipients showed that AAV9 induced a prominent and stable luciferase activity in the abdomen, when compared with AAV2 and AAV8. However, ex vivo analyses revealed that intracoronary perfusion with AAV2 resulted in the highest heart transplant transduction levels in syngrafts and allografts. Ex vivo intracoronary delivery of AAV2 resulted in efficient transgene expression in heart transplants, whereas intracoronary AAV9 escapes into adjacent tissues. In terms of cardiac transduction, these results suggest AAV2 as a potential vector for gene therapy in preclinical heart transplants studies, and highlight the importance of delivery route in gene transfer studies.     

Donor Heart Treatment With COMP‐Ang1 Limits Ischemia‐Reperfusion Injury and Rejection of Cardiac Allografts

The major cause of death during the first year after heart transplantation is primary graft dysfunction due to preservation and ischemia‐reperfusion injury (IRI). Angiopoietin‐1 is a Tie2 receptor‐binding paracrine growth factor with anti‐inflammatory properties and indispensable roles in vascular development and stability. We used a stable variant of angiopoietin‐1 (COMP‐Ang1) to test whether ex vivo intracoronary treatment with a single dose of COMP‐Ang1 in donor Dark Agouti rat heart subjected to 4‐h cold ischemia would prevent microvascular dysfunction and inflammatory responses in the fully allogeneic recipient Wistar Furth rat. COMP‐Ang1 reduced endothelial cell–cell junction disruption of the donor heart in transmission electron microscopy during 4‐h cold ischemia, improved myocardial reflow, and reduced microvascular leakage and cardiomyocyte injury of transplanted allografts during IRI. Concurrently, the treatment reduced expression of danger signals, dendritic cell maturation markers, endothelial cell adhesion molecule VCAM‐1 and RhoA/Rho‐associated protein kinase activation and the influx of macrophages and neutrophils. Furthermore, COMP‐Ang1 treatment provided sustained anti‐inflammatory effects during acute rejection and prevented the development of cardiac fibrosis and allograft vasculopathy. These results suggest donor heart treatment with COMP‐Ang1 having important clinical implications in the prevention of primary and subsequent long‐term injury and dysfunction in cardiac allografts.